Summer Intern Project 2013: Max Kerr-Winter

Density Functional Theory Model of Natively Unfolded Proteins in the Nuclear Pore complex

Supervisor: Dr B W Hoogenboom

The Nuclear Pore Complex (NPC) is a transport system between the nucleus and cell body of eukaryotic cells. It consists of a pair of rigid rings of protein, with flexible Natively Unfolded Proteins (NUPs) tethered to the rings and extending into the centre of the pore. Molecules with a diameter of less than around 6nm can diffuse through the pore, but anything larger cannot, requiring the structure of the pore to change to allow transport in or out of the nucleus. Consequently the behaviour of the NPC is crucial to many important biological processes, including protein production from DNA, and reverse transcription by retroviruses.

It is thought that the NUPs play a crucial role in selectively transporting molecules through the pore. Computer simulations have shown phase behaviour where the NUPs gather either in the centre of the pore or in clumps around the wall. The transition between these two phases could be the basis of the mechanism by which the NPC opens and closes. 

The aim of this project was to explore the phase behaviour of the NUPs as a function of pore radius and polymer-polymer interaction strength and range. The programme used was written by (UCL PhD student) D. Osmanovic in C++ and used classical Density Functional Theory (DFT) to approximate the polymer density. The programme iteratively modified the polymer density function so as to minimize the Helmholtz free energy of the system. Phase diagrams were produced to show the boundary between central and wall polymer equilibrium states for 1D, 2D rotationally symmetric, and 2D rotationally asymmetric models of the pore. 

Max Kerr-Winter: Nuclear Pore Complex DFT models

Distributions of polymer density within the NPC in central (left) and wall (right) phases.


The results agreed broadly with previously found results by D. Osmanovic and (CoMPLEX MRes Student) R. C. Eccleston, showing a clear boundary between the regions of parameter space that resulted in central or wall equilibrium states. The 1D simulation also showed a region where the central phase was stable, but the wall phase was metastable. This metastable region may play a role in allowing the NPC to selectively open and close. 

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